Sickle cell crisis is an acute exacerbation of a continuous process in the patient afflicted with the homozygous state of hemoglobin S. Neither the etiology nor the pathophysiology of crisis have been established. Starting with the assumption that crisis reflects an acute change of the properties of the circulating red blood cell, we have been able to demonstrate that: 1. Recovery from crises is intimately associated with an increased filterability of the circulating red cell, expressed by a shorter time of filtration and a higher percentage of cells filtered. 2. Recovery is associated with a decreased susceptibility of the circulating red cell to sickle. 3. The asymptomatic phase of the disease is associated with fluctuations in above measurements below those observed during crisis. 4. Development of crisis is apparently associated with changes in the properties of the red cell in the opposite direction from those observed during recovery. Preliminary studies indicate a close relationship between observations and the intracellular concentration of 2,3-DPG and ATP. There appears to be no correlation between the observed changes and the total concentration of fetal hemoglobin. Studies along these lines and with cell fractionation are in progress.